Altered Accumbens Signaling Following Ethanol Exposure

乙醇暴露后伏隔信号传导发生改变

基本信息

批准号：
7276133
负责人：
Frederic Woodward Hopf
金额：
$ 32.69万
依托单位：
ERNEST GALLO CLINIC AND RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7276133
关键词：
Abstinence Action Potentials Address Adult Agonist Alcohols Animals Apamin Appendix Behavior Biological Assay Brain Calcium Calcium Channel Cells Chronic Cocaine Condition Consumption Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Dependency Development Dopamine Dopamine D2 Receptor Dopamine Receptor Dose Electrophysiology (science)Ethanol Exposure to Fire - disasters Forskolin Goals Human Image Ion Channel Medial Mediating Methods Motivation Neurons Neurophysiology - biologic function Nomifensine Nucleus Accumbens Numbers Pharmaceutical Preparations Physiologic pulse Play Potassium Potassium Channel Predisposition Property Proteins Pulse taking Rattus Receptor Signaling Regulation Relapse Relative (related person)Research Personnel Role Self Administration Self-Administered Signal Transduction Slice Source Stimulus Sucrose System Time Training Week Western Blotting Wistar Rats addiction alcohol craving alcohol exposure behavior influence craving day deprivation dopamine transporter drug of abuse inhibitor/antagonist mature animal motivated behavior patch clamp problem drinker programs receptor receptor function research study uptake voltage clamp weanling animal

项目摘要

DESCRIPTION (provided by applicant): Human alcoholics attempting to maintain abstinence often undergo major periods of craving, relapse and continued consumption. To address these problems, it is important to identify alterations in neural function that persist after ethanol exposure has ceased, as these changes are likely to enhance susceptibility to relapse-inducing stimuli. Functional changes within the nucleus accumbens (NAcb) could potently alter nduction of relapse, as the NAcb is implicated in responsiveness to many conditioned stimuli, as well as consumption of and reinstatement for drugs of abuse, and several human imaging studies suggest a role for the NAcb in cravings in alcoholics and cocaine addicts. The major goal of this proposal is to determine whether basic spike firing and dopaminergic modulation of firing in the NAcb are persistently altered during abstinence following repeated ethanol exposure. We focus on spike firing, as it is the predominant mechanism by which neurons transmit information. Spike firing will be analyzed using patchclamp electrophysiology in NAcb brain slices from adult animals that operantly self-administered ethanol for 40-45 days, then underwent 3 weeks of abstinence. Animals self-administering sucrose then undergoing abstinence will act as a control. Our preliminary data provide the first evidence that spike firing in NAcb core neurons is enhanced during abstinence following repeated ethanol exposure, which may be due to inhibition of a calcium-dependent potassium current (I[SKICa2+]). Specific aim 1 will examine whether basic spike firing properties in the NAcb are altered after 3 and 6 months of abstinence following ethanol self-administration. Specific aim 2 will use voltage-clamp methods and specific antagonists to characterize the calcium sources that contribute to I[SKCa2+[ activation, and which might be reduced in ethanol-trained animals during abstinence. Specific aim 3 will investigate whether modulation of spike firing by dopamine is altered following repeated ethanol exposure, as dopamine signaling within the NAcb regulates reinstatement for several drugs of abuse, and NAcb dopamine can contribute strongly during ethanol self-administration. Altered spike firing and dopamine signaling in the NAcb could significantly influence the behavioral contribution of the NAcb, and in this way facilitate the onset of relapse.

描述（由申请人提供）：试图维持禁欲的人类酗酒者经常会经历重大渴望，复发和继续消费。为了解决这些问题，重要的是要确定乙醇暴露后持续存在的神经功能的改变，因为这些变化可能会增强对复发刺激的敏感性。伏隔核（NACB）内部的功能变化可以有效改变复发的NACB，因为NACB与对许多条件刺激的反应性有关，以及对滥用药物的消耗和恢复的消费和恢复，并且一些人类成像研究表明，NACB在酒精中毒和cocaine成瘾者中的NACB对NACB的作用。该提案的主要目的是确定在反复暴露乙醇后，在禁欲期间，NaCB中的基本尖峰点火和多巴胺能调节是否会持续改变。我们专注于尖峰射击，因为它是神经元传输信息的主要机制。将使用PatchClamp电生理学分析峰值射击，该动物的NACB脑切片中的NACB脑切片，这些动物是自我管理的乙醇40-45天，然后进行了3周的禁欲。动物自我管理的蔗糖随后进行禁欲将充当控制。我们的初步数据提供了第一个证据，表明在反复暴露乙醇后，NACB核心神经元中的峰值发射增强，这可能是由于抑制钙依赖性钾电流（I [Skica2+]）。具体的目标1将检查乙醇自我给药3和6个月后，NACB中的基本尖峰发射特性是否会改变。特定的目标2将使用电压钳方法和特定的拮抗剂来表征有助于I [SKCA2+[激活，并且在节制期间受乙醇训练的动物中可能会降低的钙源。具体目标3将调查反复暴露乙醇后，多巴胺对峰值发射的调节是否会改变，因为NACB内的多巴胺信号传导调节了几种滥用药物的恢复原状，而NACB多巴胺在乙醇自我服药过程中可以强烈贡献。 NACB中的尖峰发射和多巴胺信号的变化可能会显着影响NACB的行为贡献，以此方式促进了复发的开始。